Normative Gray Matter Stiffness Gradients in the Human Brain Predict Patterns of Cortical Injury after Concussion

Area of Science:

• Neuroimaging
• Biophysics
• Neurology

Background:

• Traumatic brain injury (TBI) often leads to neurodegeneration, primarily affecting gray matter.
• Acute gray matter damage after mild TBI (mTBI) is difficult to detect with conventional diffusion tensor imaging (DTI) due to limitations in resolving cortical microarchitecture.
• Conventional DTI metrics are insensitive to the complex solid-phase matrix of gray matter, hindering the study of acute injury.

Purpose of the Study:

• To investigate whether constrained spherical deconvolution (CSD)-derived "total" apparent fiber density (AFD) can index gray matter microarchitecture and detect acute damage after mTBI.
• To test the hypothesis that regional AFD measurements covary with magnetic resonance elastography (MRE)-derived cortical stiffness in healthy adults.
• To evaluate AFD's ability to detect gray matter injury missed by traditional tensor metrics across different mTBI recovery stages.

Main Methods:

• Relating AFD from diffusion MRI in 349 healthy adults to MRE-derived shear modulus in an independent cohort of 59 healthy adults.
• Analyzing three cross-sectional mTBI cohorts (acute, subacute, chronic) compared to age- and sex-matched controls.
• Utilizing Cohen's *d* for effect size thresholding (|*d*| ≥ 2.0) to identify robust microstructural alterations in cortical parcels and white matter tracts.

Main Results:

• Regional AFD distribution explained 74% of the variance in MRE-measured cortical stiffness, confirming AFD's coupling to microstructural features influencing tissue rigidity.
• In mTBI cohorts, AFD detected significant gray matter disruption across acute (11 parcels), subacute (116 parcels), and chronic (>106 parcels) stages, outperforming DTI metrics.
• MRE-based stiffness in healthy controls predicted the direction and magnitude of AFD changes post-mTBI, with stiffer regions showing persistent decreases and less stiff regions showing recovery-related increases.

Conclusions:

• Constrained spherical deconvolution (CSD)-derived "total" apparent fiber density (AFD) provides in vivo evidence of acute gray matter damage after mild traumatic brain injury (mTBI).
• Joint analysis of diffusion MRI and MRE sharpens mechanistic interpretations of gray matter microarchitecture and detects disruption across the mTBI timeline.
• AFD represents a promising tool for assessing gray matter integrity and tracking recovery following mTBI, overcoming limitations of conventional diffusion tensor metrics.